Nakajo syndrome

Synonyms

7

Overview

Nakajo-Nishimura syndrome (NNS) is an inherited condition that affects many parts of the body and has been described only in the Japanese population. Beginning in infancy or early childhood, affected individuals develop red, swollen lumps (nodular erythema) on the skin that occur most often in cold weather; recurrent fevers; and elongated fingers and toes with widened and rounded tips (clubbing).

 Later in childhood, affected individuals develop joint pain and joint deformities called contractures that limit movement, particularly in the hands, wrists, and elbows. They also experience weakness and wasting of muscles, along with a loss of fatty tissue (lipodystrophy), mainly in the upper body. The combination of muscle and fat loss worsens over time, leading to an extremely thin (emaciated) appearance in the face, chest, and arms.

 Other signs and symptoms of Nakajo-Nishimura syndrome can include an enlarged liver and spleen (hepatosplenomegaly), a shortage of red blood cells (anemia), a reduced amount of blood clotting cells called platelets (thrombocytopenia), and abnormal deposits of calcium (calcification) in an area of the brain called the basal ganglia. Intellectual disability has been reported in some affected individuals.

Nakajo-Nishimura syndrome appears to be rare and has been described only in the Japanese population. About 30 cases have been reported in the medical literature. Consanguinity or familial history is observed in about seventy percent of the affected families.

Symptoms

Onset appears in early infancy with pernio-like lesions (mainly on fingertips and earlobes) that usually appear during the first winter after birth. This is followed by periodic fever and nodular erythema with infiltration and induration. Progressive lipomuscular atrophy (mainly in the upper body) and interphalangeal joint contractures lead to the characteristic thin and angular facial appearance and to the long clubbed fingers seen eventually in all patients. Central obesity and myositis, leading to muscle weakness, is also noted in some. Other less common manifestations include short stature, heliotrope-like rash on eyelids, severe tylosis on feet and hyperhidrosis of hands and feet. Hepatosplenomegaly is also reported. Lipodystrophy is progressive and irreversible.

Causes

Nakajo-Nishimura syndrome is caused by mutations in the PSMB8 gene. This gene provides instructions for making one part (subunit) of specialized cell structures called immunoproteasomes, which are found primarily in immune system cells. Immunoproteasomes play an important role in regulating the immune system's response to foreign invaders, such as viruses and bacteria. One of the primary functions of immunoproteasomes is to help the immune system distinguish the body's own proteins from proteins made by foreign invaders, so the immune system can respond appropriately to infection.

 Mutations in the PSMB8 gene greatly reduce the amount of protein produced from the PSMB8 gene, which impairs the normal assembly of immunoproteasomes and causes the immune system to malfunction. For unknown reasons, the malfunctioning immune system triggers abnormal inflammation that can damage the body's own tissues and organs; as a result, Nakajo-Nishimura syndrome is classified as an autoinflammatory disorder. Abnormal inflammation likely underlies many of the signs and symptoms of Nakajo-Nishimura syndrome, including the nodular erythema, recurrent fevers, joint problems, and hepatosplenomegaly.

 Nakajo-Nishimura syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Prevention

NNS is inherited in an autosomal recessive manner and genetic counseling is possible.

Prenatal diagnosis is possible but has never been performed.

Diagnosis

A clinical diagnosis of NNS can be made if at least 5 of the following 8 features are positive:

1. Autosomal recessive inheritance (parental consanguinity and/or familial occurrence)

2. Pernio-like purplish rash in hands and feet (appearing in winter since infancy)

3. Haunting nodular erythema with infiltration and induration (sometimes circumscribed)

4. Repetitive spiking fever (periodic, not necessarily)

5. Long clubbed fingers and toes with joint contractures

6. Progressive partial lipomuscular atrophy and emaciation (marked in the upper part of body)

7. Hepatosplenomegaly

8. Basal ganglia calcification

 Not all of these features are apparent until childhood. Histopathologic examination reveals focal mononuclear cell infiltration with vasculopathy. Laboratory findings include constantly elevated C-reactive protein (CRP) levels and hyper-gamma-globulinemia. Autoantibody titers increase as the disease progresses in some but remain negative in others. Molecular genetic testing can identify a disease causing mutation, confirming diagnosis.

Prognosis

Although some of the symptoms of NNS can be lessened with treatment, the prognosis remains relatively poor. Some may die from sudden cardiac failure, probably due to lung insufficiency.

Treatment

There is no effective therapeutic regimen for NNS. Fever and skin lesions respond well to systemic steroid administration but usually reoccur after tapering. Also, there are many side effects (growth retardation, glaucoma and central obesity) associated with long-term systemic steroid use. Tocilizumab has shown efficacy in some patients. Although kallidinogenase and dapsone have been reported to be effective in some, the effect is temporary. These treatments are all ineffective in halting lipodystrophy progression.

Resources

[1] https://ghr.nlm.nih.gov/condition/nakajo-nishimura-syndrome#

[2] Kanazawa N – Nakajo-Nishimura Syndrome: An Autoinflammatory Disorder Showing Pernio-Like Rashes and Progressive Partial Lipodystrophy. Allergology International. 2012;61:197-206.

[3] http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2615